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Attenuation of Forkhead signaling by the retinal determination factor DACH1.

Research paper by Jie J Zhou, Chenguang C Wang, Zhibin Z Wang, Will W Dampier, Kongming K Wu, Mathew C MC Casimiro, Iouri I Chepelev, Vladimir M VM Popov, Andrew A Quong, Aydin A Tozeren, Keji K Zhao, Michael P MP Lisanti, Richard G RG Pestell

Indexed on: 31 Mar '10Published on: 31 Mar '10Published in: PNAS



Abstract

The Drosophila Dachshund (Dac) gene, cloned as a dominant inhibitor of the hyperactive growth factor mutant ellipse, encodes a key component of the retinal determination gene network that governs cell fate. Herein, cyclic amplification and selection of targets identified a DACH1 DNA-binding sequence that resembles the FOX (Forkhead box-containing protein) binding site. Genome-wide in silico promoter analysis of DACH1 binding sites identified gene clusters populating cellular pathways associated with the cell cycle and growth factor signaling. ChIP coupled with high-throughput sequencing mapped DACH1 binding sites to corresponding gene clusters predicted in silico and identified as weight matrix resembling the cyclic amplification and selection of targets-defined sequence. DACH1 antagonized FOXM1 target gene expression, promoter occupancy in the context of local chromatin, and contact-independent growth. Attenuation of FOX function by the cell fate determination pathway has broad implications given the diverse role of FOX proteins in cellular biology and tumorigenesis.